Date of Award
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Neuroscience
First Advisor
Margaret A. Vizzard
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, inflammatory lower urinary tract (LUT) disorder of unknown etiology characterized by symptoms of increased voiding urgency, frequency, and pelvic pain. Purported mechanisms include a cycle of afferent nerve hypersensitization and bladder inflammation. There are no current globally effective treatments for IC/BPS, which presents an enormous social and healthcare burden. Prevalence estimates vary widely due to inconsistent diagnostic criteria; however, up to 6.5% of the population may be affected, with a ratio of up to 10:1 female to male patients. Psychological stress is known to exacerbate the negative signs and symptoms of IC/BPS, but the mechanism by which this arises is unclear.
In this dissertation, we validated a 2-week repeated variate stress (RVS) model in adult female mice which induced urinary bladder dysfunction as measured by conscious, open-outlet, continuous-infusion cystometry. RVS mice showed a significantly decreased intermicturition interval (IMI) and infused volume between voids (IV) (p < 0.05). We also found increased corticosterone expression in the serum and fecal pellets of RVS mice (p < 0.05), as well as anxiety-like behavior evidenced at the end of the 2-week paradigm. Next, we examined the role of the transient receptor potential ion channel TRPV1 in RVS-induced bladder dysfunction. TRPV1 is a thermal nociceptor widely distributed on sensory afferent nerves in the LUT and a promising target in IC/BPS therapies due to its role in burning pain sensation and signaling. We quantified TRPV1 protein expression in the lumbosacral spinal cord and dorsal root ganglia and found an RVS-dependent increase in spinal cord levels L1 and L2 and dorsal root ganglia level L2. We pharmacologically antagonized the TRPV1 channel with the compound capsazepine after RVS and found that intervention rescued IMI and IV to control levels. We then validated these findings with TRPV1 global knockout (KO) mice, which did not show RVS-induced bladder dysfunction. Fecal and serum corticosterone levels did not differ between TRPV1 control and TRPV1 KO RVS animals despite an anxiety-like phenotype displayed after RVS.
These studies demonstrated bladder dysfunction after a 2-week RVS paradigm in wild-type adult female mice. The intravesical instillation of the TRPV1 receptor antagonist capsazepine rescued IMI and IV in RVS animals and TRPV1 KO animals did not exhibit bladder dysfunction after RVS. Increased TRPV1 expression in levels L1 and L2 of the spinal cord and L2 of the dorsal root ganglia after RVS implicate IC/BPS as a disorder of the storage arm of the micturition reflex. Together, the results of this dissertation suggest an important role of TRPV1 in RVS-induced bladder dysfunction.
Language
en
Number of Pages
196 p.
Recommended Citation
Sidwell, Amanda, "The role of the transient receptor potential ion channel TRPV1 in repeated variate stress-induced micturition reflex dysfunction in adult female mice" (2024). Graduate College Dissertations and Theses. 1866.
https://scholarworks.uvm.edu/graddis/1866